Molecular Dynamics Simulations Indicate the SARS-CoV-2 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

Maria Bzówka; Karolina Mitusinska; Agata Raczynska; Aleksandra Samol; Jack Tuszynski; Artur Góra

As reported in the previous research, the overall plasticity of Mpro is required for proper enzyme functioning [37, 38] . In the case of SARS-CoV the truncation of the linker loop (F185-T201) gave rise to a significant reduction in protein activity and confirmed that the proper orientation of the linker allows the shift between dimeric and monomeric forms [39] . Dimerisation of the enzyme is necessary for its catalytic activity and the proper conformation of the seven N-terminal residues (N-finger) is required [40] . In SARS-CoV-2 Mpro, the T285 is replaced by alanine, and the I286 by leucine. It has been shown that replacing S284, T285, and I286 by alanine residues in SARS-CoV Mpro leads to a 3.6-fold enhancement of the catalytic activity of the enzyme. This is accompanied by changes in the structural dynamics of the enzyme that transmit the effect of the mutation to the catalytic centre. Indeed, the T285A replacement observed in the SARS-CoV-2 Mpro allows the two domains III to approach each other a little closer [41] .